Catecholamine induces Kupffer cell apoptosis via growth differentiation factor 15 in alcohol-associated liver disease

Abstract

Chronic alcohol consumption often induces hepatic steatosis but rarely causes severe inflammation in Kupffer cells (KCs) despite the increased hepatic influx of lipopolysaccharide (LPS), suggesting the presence of a veiled tolerance mechanism. In addition to LPS, the liver is affected by several gut-derived neurotransmitters through the portal blood, but the effects of catecholamines on KCs have not been clearly explored in alcohol-associated liver disease (ALD). Hence, we investigated the regulatory roles of catecholamine on inflammatory KCs under chronic alcohol exposure. We discovered that catecholamine levels were significantly elevated in the cecum, portal blood, and liver tissues of chronic ethanol-fed mice. Increased catecholamines induced mitochondrial translocation of cytochrome P450 2E1 in perivenous hepatocytes expressing the β2-adrenergic receptor (ADRB2), leading to the enhanced production of growth differentiation factor 15 (GDF15). Subsequently, GDF15 profoundly increased ADRB2 expression in adjacent inflammatory KCs to facilitate catecholamine/ADRB2-mediated apoptosis. Single-cell RNA sequencing of KCs confirmed the elevated expression of Adrb2 and apoptotic genes after chronic ethanol intake. Genetic ablation of Adrb2 or hepatic Gdf15 robustly decreased the number of apoptotic KCs near perivenous areas, exacerbating alcohol-associated inflammation. Consistently, we found that blood and stool catecholamine levels and perivenous GDF15 expression were increased in patients with early-stage ALD along with an increase in apoptotic KCs. Our findings reveal a novel protective mechanism against ALD, in which the catecholamine/GDF15 axis plays a critical role in KC apoptosis, and identify a unique neuro-metabo-immune axis between the gut and liver that elicits hepatoprotection against alcohol-mediated pathogenic challenges.

Kluyveromyces marxianus supplementation ameliorates alcohol-induced liver injury associated with the modulation of gut microbiota in mice

“…LPS/TLR4-mediated inflammatory activation of Kupffer cells further aggravates ALD by activating downstream NF-κB pathways. 23 In this research, the protein expression levels of TLR4, MyD88 and NF-κB significantly increased after alcohol exposure ( p < 0.05, Fig. 4A–D).…”

Exosome-Based Delivery of Super-Repressor IκBα Alleviates Alcohol-Associated Liver Injury in Mice

“…Moreover, all of the pathologic findings, including lipid accumulation, apoptosis, and infiltration of MPO + neutrophils, were found in the hepatic midzonal area of Exo-Naïve-treated mice. These results may indicate that there might be a functional heterogeneity in KCs depending on their locations across the hepatic lobules in ALD; perivenous KCs undergo apoptosis, midzonal KCs provoke inflammation, and periportal KCs limit endotoxin levels by phagocytosis [ 36 , 37 ]. It would be interesting to define the functional and spatial heterogeneity of KCs in detail by utilizing spatial multi-omics technology for more precise targeting of inflammatory KCs in ALD.…”

Macrophages as a Source and Target of GDF-15

“…Kim et al proposed a mechanism linking liver fibrosis to increased levels of liver and portal catecholamines along with GDF-15 [130]. This association was explained by the increased ethanolinduced oxidative stress in the mitochondria, with catecholamines facilitating increased levels of CYP2E1, which correlated with increased GDF-15 levels.…”

“…These findings shed light on the mechanism by which GDF-15 functions as a stress-induced cytokine, promoting apoptosis of inflammatory Kupffer cells. These cells play a key role in the fibrotic changes of alcohol-induced liver injury, thereby mitigating further hepatic damage [130].…”